5osc

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GLIC-GABAAR alpha1 chimera crystallized in complex with pregnenolone sulfate at pH 4.5

Structural highlights

5osc is a 5 chain structure with sequence from Gloeobacter violaceus PCC 7421 and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Ligands:A8W, ACT, CL, Y01
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GBRA1_MOUSE Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:27129275). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:27129275). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (PubMed:27129275). The alpha1/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:27129275). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (PubMed:25348603). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).[UniProtKB:P62813][1] [2] GLIC_GLOVI Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.[3] GBRA2_MOUSE Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:27129275). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:27129275). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (PubMed:27129275). The alpha2/beta2/gamma2 receptor exhibits synaptogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity (PubMed:27129275).[4]

Publication Abstract from PubMed

gamma-Aminobutyric acid receptors (GABAARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABAARs is the alpha subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAAR function requires high-resolution structures. Here we present the first atomic structures of a GABAAR chimera at 2.8-A resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the alpha-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABAARs in neurological disorders.

Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.,Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG Nat Struct Mol Biol. 2017 Oct 2. doi: 10.1038/nsmb.3477. PMID:28967882[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Swanson AM, Allen AG, Shapiro LP, Gourley SL. GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Neuropsychopharmacology. 2015 Mar;40(4):1027-36. PMID:25348603 doi:10.1038/npp.2014.292
  2. ↑ Brown LE, Nicholson MW, Arama JE, Mercer A, Thomson AM, Jovanovic JN. γ-Aminobutyric Acid Type A (GABAA) Receptor Subunits Play a Direct Structural Role in Synaptic Contact Formation via Their N-terminal Extracellular Domains. J Biol Chem. 2016 Jul 1;291(27):13926-13942. PMID:27129275 doi:10.1074/jbc.M116.714790
  3. ↑ Bocquet N, Prado de Carvalho L, Cartaud J, Neyton J, Le Poupon C, Taly A, Grutter T, Changeux JP, Corringer PJ. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature. 2007 Jan 4;445(7123):116-9. Epub 2006 Dec 10. PMID:17167423 doi:10.1038/nature05371
  4. ↑ Brown LE, Nicholson MW, Arama JE, Mercer A, Thomson AM, Jovanovic JN. γ-Aminobutyric Acid Type A (GABAA) Receptor Subunits Play a Direct Structural Role in Synaptic Contact Formation via Their N-terminal Extracellular Domains. J Biol Chem. 2016 Jul 1;291(27):13926-13942. PMID:27129275 doi:10.1074/jbc.M116.714790
  5. ↑ Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat Struct Mol Biol. 2017 Oct 2. doi: 10.1038/nsmb.3477. PMID:28967882 doi:http://dx.doi.org/10.1038/nsmb.3477

Contents


PDB ID 5osc

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